JP4594736B2 - Stabilized anthracycline-based lyophilized formulations - Google Patents

Description

  The present invention relates to a stabilized preparation of amrubicin or a salt thereof useful as a cancer chemotherapeutic agent.

Following formula (1):
(7S, 9S) -9-acetyl-9-amino-7-[(2-deoxy-β-D-erythro-pentopyranosyl) oxy] -7,8,9,10-tetrahydro-6,11- Dihydroxy-5,12-naphthacenedione (hereinafter referred to as amrubicin) and salts thereof are known to be useful as cancer chemotherapeutic agents (for example, Japanese Patent Publication No. 3-5397 (corresponding US Pat. , 673, 668).). Such amrubicin hydrochloride has several crystal forms, and it is also known that certain crystals have excellent thermal stability (for example, Japanese Patent No. 2975018 (corresponding US Pat. 952, 566)).
Anthracycline-based compounds such as amrubicin are unstable in solution. However, when formulating such a compound as an injection, there is a method in which powder-filled or lyophilized powder is used to make an injection that is soluble upon use. Generally done.
As a stabilized preparation of amrubicin, a preparation containing L-cysteine or a salt thereof is known (see, for example, Japanese Patent No. 2603480 (corresponding US Pat. No. 6,376,469)).

On the other hand, as a typical degradation product of amrubicin, the following formula (2):
(Hereinafter referred to as deglycosylated (2)) and the following formula (3):
There was a deamination product (hereinafter referred to as a deamination product (3)), and these decomposition products tended to increase during the production process and storage process of amrubicin preparations. From the viewpoint of quality assurance of pharmaceuticals, it is extremely important to suppress the increase of these degradation products as long as possible over the long term, and development of a method for further stabilizing an amrubicin preparation has been desired.
In addition to amrubicin, there are anthracycline anticancer agents that have been clinically applied. Commercial anthracycline anticancer agents other than amrubicin have a structure having a hydroxyl group at the 9-position of anthracycline, as shown below, whereas amrubicin has a structural difference that it has an amino group at the 9-position. Therefore, only amrubicin produces the deaminated product (3) as a degradation product, which is linked to the difference in stability from other anthracycline anticancer agents.
Actually, regarding anthracycline anticancer agents (both injectable preparations) sold in Japan, the pH when dissolved in water for injection or physiological saline is as follows (Japan Medical Information Center, “Medical Yakuhin Pharmaceuticals (24th edition) ", 2001 edition).
Aclarubicin hydrochloride 5.0-6.5
Idarubicin hydrochloride 5.0-7.0
Epirubicin hydrochloride 4.5-6.0
Daunorubicin hydrochloride 5.0-6.5
Doxorubicin hydrochloride 5.0-6.0
Pirarubicin hydrochloride 5.0-6.5
On the other hand, in the case of amrubicin hydrochloride, since the production of deaminated compound (3) tends to increase at pH 3.5 or higher, it is unstable at a high pH as seen in the above-mentioned anthracycline anticancer agents, and clinical administration When the lyophilized preparation for use is dissolved in a physiological saline solution or a 5% glucose injection solution, the pH is 2.4 to 3.0.
That is, compared to other anthracycline anticancer agents, the stable pH of amrubicin hydrochloride is biased toward the acidic side, and the stable pH range is narrow. As described above, since the stability of the active ingredient is different, it is necessary to study conditions specific to amrubicin different from other anthracycline anticancer agents when developing a method for stabilizing an amrubicin preparation.
As a method for stabilizing an amrubicin preparation, as described above, a method of adding L-cysteine or a salt thereof to the preparation is known. Although this method can suppress the production of the deaminated product (3), the production of the deglycosylated product (2) may increase depending on the conditions.
Due to the market launch of amrubicin preparations, it became necessary to conduct studies on the implementation of industrial production methods. Then, as a result of continuing intensive studies on the method for further stabilizing the L-cysteine-containing preparation, the present inventors have found the following surprising findings and have completed the present invention.
(1) Moisture contained in a freeze-dried amrubicin greatly affects the production of deglycosides (2). If the water content is controlled within a certain range, the production of deglycosides (2) is suppressed and long-term storage is achieved. Sometimes a stable lyophilized product is obtained.
(2) On the other hand, in the manufacturing process of the lyophilized preparation, the temperature of the process in the solution state affects the production of the decomposition product (mainly deaminated product (3)), and the process is carried out at a sufficiently low temperature. Production of the degradation product in the process is suppressed, and as a result, the content of final degradation products (deglycosylated (2) and deaminated (3)) after long-term storage of the lyophilized preparation can be suppressed.
That is, the present invention is as follows.
[1] A freeze-dried preparation containing amrubicin or a salt thereof, which has the following characteristics:
(1) contains L-cysteine or a salt thereof; and (2) the water content in the preparation is 0 to about 4% by weight based on the weight of the lyophilized powder.
[2] The stabilized preparation according to item [1], wherein water in the preparation is 0 to about 3.5% by weight with respect to the weight of the lyophilized powder.
[3] The stabilized preparation according to item [1], wherein water in the preparation is about 0.5 to about 3.5% by weight based on the weight of the lyophilized powder.
[4] The stabilized preparation according to item [1], wherein water in the preparation is about 0.5 to about 2.0% by weight based on the weight of the lyophilized powder.
[5] The stabilized preparation according to any one of items [1] to [4], wherein the content of L-cysteine or a salt thereof is about 0.5 to about 250 mg with respect to 100 mg (titer) of amrubicin or a salt thereof. .
[6] The stabilized preparation according to any one of items [1] to [4], wherein the content of L-cysteine or a salt thereof is about 3 to about 45 mg per 100 mg (titer) of amrubicin or a salt thereof.
[7] The stabilized preparation according to any one of items [1] to [6], wherein the salt of amrubicin is hydrochloride.
[8] The stabilized preparation according to any one of items [1] to [7], wherein the salt of L-cysteine is hydrochloride.
[9] L-cysteine or a salt thereof is (1) L-cysteine in the range of about 5 to about 20 mg or (2) an L-cysteine salt in an amount corresponding to 100 mg titer of amrubicin hydrochloride. The stabilized preparation according to any one of Items [1] to [8].
[10] The stabilized preparation according to any one of items [1] to [9], further comprising an excipient.
[11] The stabilized preparation according to item [10], wherein the excipient is lactose.
[12] The salt of amrubicin has a diffraction angle (2θ) of 6.3 ± 0.3, 10.1 ± 0.3, 20.3 ± 0.3, 26.5 ± 0.00 in the powder X-ray diffraction pattern. The stabilized preparation according to any one of Items [1] to [11], which is crystalline amrubicin hydrochloride having a main peak at 3 and 26.9 ± 0.3 degrees.
[13] Items [1] to [12] are prepared by preparing an aqueous solution containing (a) amrubicin or a salt thereof, and (b) L-cysteine or a salt thereof, and subjecting the aqueous solution to aseptic filtration and lyophilization. ] The manufacturing method of the stabilized formulation in any one of.
[14] The method for producing a stabilized preparation according to any one of items [1] to [12], comprising the following steps (1) to (4):
(1) (a) amrubicin or a salt thereof, and (b) L-cysteine or a salt thereof is dissolved in water to prepare an aqueous solution,
(2) Adjust the pH of the aqueous solution of (1) to about 2 to about 5,
(3) Aseptically filter the aqueous solution of (2),
(4) The aqueous solution obtained in (3) is freeze-dried.
[15] The process according to item [14], wherein the salt of amrubicin is hydrochloride.
[16] The production method according to item [14] or [15], wherein the salt of L-cysteine is hydrochloride.
[17] The production method according to any one of items [14] to [16], wherein the pH is adjusted to about 2.0 to about 3.5 in the step (2).
[18] The production method according to any one of items [14] to [16], wherein the pH is adjusted to about 2.2 to about 3.0 in the step (2).
[19] The method according to any one of items [14] to [18], wherein the steps (1) to (3) are performed at about 15 ° C. or lower.
[20] The production method according to any one of items [14] to [18], wherein the steps (1) to (3) are carried out at about 10 ° C. or lower.
[21] The salt of amrubicin has a diffraction angle (2θ) of 6.3 ± 0.3, 10.1 ± 0.3, 20.3 ± 0.3, 26.5 ± 0.00 in the powder X-ray diffraction pattern. Item 15. The production method according to any one of Items [14] to [20], which is crystalline amrubicin hydrochloride having a main peak at 3 and 26.9 ± 0.3 degrees.
[22] A method for producing a stable lyophilized preparation of amrubicin, comprising the following steps (1) to (4):
(1) An aqueous solution containing amrubicin hydrochloride, L-cysteine (or an equivalent amount of L-cysteine salt) in the range of about 5 to about 20 mg with respect to 100 mg titer of amrubicin hydrochloride, and an excipient,
(2) adjusting the pH of the aqueous solution of (1) to about 2.0 to about 3.5;
(3) Aseptically filter the aqueous solution of (2),
(4) The aqueous solution obtained in (3) is freeze-dried to obtain a freeze-dried preparation in which the water content in the preparation is 0 to about 4% by weight based on the weight of the freeze-dried powder.
[23] The production method according to item [22], wherein the excipient is lactose.
[24] A cancer chemotherapeutic agent comprising the stabilized preparation according to any one of items [1] to [12].
[25] A cancer chemotherapeutic agent comprising a freeze-dried preparation produced by the production method according to any one of items [13] to [23].

FIG. 1 shows the deglycosides (2) that are one of the degradation products when amrubicin lyophilized preparations containing various amounts of water are subjected to stability test at 40 ° C. (Experimental Examples 2 and 3). Represents the amount produced. The horizontal axis represents elapsed time / month. Each polygonal line represents data for the following formulations, respectively.
●: Hydrated formulation B of Experimental Example 2 (starting moisture = 5.0%)
○: Hydrated formulation A of Experimental Example 2 (starting moisture = 3.5%)
Δ: Blank of Experimental Example 2 (water-free preparation) (water content at the start = 1.3%)
X: Formulation obtained in Example 2 (starting moisture = 0.7%)
◆: Formulation obtained in Example 3 (starting moisture = 0.6%)

The present invention is described in further detail below.
In the present specification, unless otherwise specified, “moisture” in the preparation represents weight% with respect to the weight of the lyophilized powder. The content of the deglycosylated body (2) and the deaminated body (3) represents the weight% relative to amrubicin.
The water content in the formulation is 0 to about 4% by weight, preferably 0 to about 3.5% by weight, more preferably about 0.5 to about 3.5% by weight, and even more preferably about 0.5 to about 2.0%. Weight percent is effective.
Examples of acids that can be used for the salt of amrubicin include hydrobromic acid, citric acid, tartaric acid, lactic acid, fumaric acid, maleic acid, methanesulfonic acid and the like in addition to hydrochloric acid. In the case of amrubicin hydrochloride, β-type crystalline amrubicin hydrochloride (diffraction angle (2θ) in powder X-ray diffraction diagram: 6.3 ± 0.3, 10.1 ± 0.3, which is a more stable crystal form) It is more preferable to use crystalline amrubicin hydrochloride (Japanese Patent No. 2975018) having main peaks at 20.3 ± 0.3, 26.5 ± 0.3 and 26.9 ± 0.3 degrees. The powder X-ray diffraction pattern can be measured by using an R-ray diffraction apparatus RINT2500V manufactured by Rigaku Electric Co., Ltd. using 1.541 ・ of Cu · Kα.
As the salt of L-cysteine, hydrochloride is usually used, and examples of other salts include sulfate. L-cysteine or a salt thereof may be a solvate such as a hydrate thereof. For example, preferred is L-cysteine hydrochloride monohydrate.
The addition amount and addition method of L-cysteine or a salt thereof are not particularly limited. However, from the relationship of the stability of amrubicin or the pharmacological activity of the additive, for example, about 0.5 with respect to 100 mg of amrubicin hydrochloride (titer). ˜about 250 mg, preferably about 3 to about 80 mg, more preferably about 3 to about 45 mg is suitable. Particularly preferably, it is appropriate to add L-cysteine salt in an amount of L-cysteine in the range of about 5 to about 20 mg, or the equivalent to 100 mg titer of amrubicin hydrochloride. Here, “the amount of L-cysteine corresponding to that” means that the amount of L-cysteine contained is equimolar. For example, 157.6 mg of “equivalent amount” of L-cysteine hydrochloride is 127.6 mg of L-cysteine, and similarly 175.6 mg of “equivalent amount” of L-cysteine hydrochloride monohydrate is is there. When L-cysteine hydrochloride monohydrate is used as the L-cysteine salt, the amount corresponding to “L-cysteine in the range of about 5 to about 20 mg” refers to about L-cysteine hydrochloride monohydrate. 2—about 29 mg.
In view of the characteristics of amrubicin, it is desirable that the pH is adjusted between about 2 and about 5, more preferably about pH 2.0 to about 3.5, and even more preferably about pH 2. A range of 2 to about 3.0, particularly preferably about pH 2.4 to about 3.0 is mentioned. In this case, a base and / or an acid may be added as a pH adjuster.
Here, examples of the base that can be used as a pH regulator in the present invention include hydroxides of alkali metals (for example, sodium and potassium), hydroxides of alkaline earth metals (for example, magnesium and calcium), and weak acids. And alkali metal salts of the above. Examples of weak metal alkali metal salts include carbonates, hydrogen carbonates, phosphates, hydrogen phosphates, dihydrogen phosphates, citrates, hydrogen citrates, and dihydrogen citrates. . These may be hydrates, and any two or more of them can be mixed and used.
Specific examples of the base that can be used as a pH regulator include, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydrogen phosphate, potassium hydrogen phosphate, phosphoric acid. Examples thereof include sodium, sodium citrate, sodium dihydrogen citrate, calcium hydroxide, hydrates thereof, and a mixture thereof. Examples of preferred bases include sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and the like. More preferably, sodium hydroxide or potassium hydroxide is mentioned.
Examples of the acid that can be used as a pH adjuster in the present invention include hydrochloric acid and sulfuric acid.
In the lyophilized preparation of the present invention, if necessary, additives such as excipients that can be added as usual preparation components may be added. Examples of the excipient include lactose, sucrose, palatinose, glucose, maltose, fructose, mannitol, erythritol, xylitol, maltitol, inositol, dextran, sorbitol, albumin, and mixtures thereof. Preferred excipients include lactose, sucrose, glucose, maltose, fructose, mannitol, xylitol, inositol, dextran, and mixtures thereof. More preferably, lactose, mannitol and a mixture thereof are used.
A method for producing a lyophilized preparation is, for example, by dissolving amrubicin or a salt thereof, L-cysteine or a salt thereof, and, if necessary, an excipient or the like in distilled water for injection, adjusting the pH with a small amount of base and / or acid, A sterile filtered solution is filled in a vial and freeze-dried to prepare a preparation in a powder form. The injection is stored in this state, dissolved in water at the time of use, and used for administration. At this time, in order to suppress decomposition in a solution state, the steps from dissolution to just before freeze-drying are preferably performed at about 15 ° C. or less, more preferably about 10 ° C. or less.
The stabilized lyophilized preparation containing amrubicin or a salt thereof of the present invention can be used as a cancer chemotherapeutic agent for the treatment of various cancer diseases. The cancer to be treated is not particularly limited, and examples thereof include cancer diseases including blood cancer and solid cancer. The dosage when used in the treatment of humans, for intravenous administration, for example, a human body surface area ^{m 2} per daily dose 5 to 300 mg, preferably 20 to 250 mg, more preferably continuous infusion in the range of 35~160mg Can be administered and treated. Examples of the administration schedule include single administration, administration once a day for 3 days, and the like.

Hereinafter, the present invention will be described with reference to examples, but the present invention is not limited thereto. In the following Examples and Experimental Examples, β-type crystalline amrubicin hydrochloride produced by the method described in Japanese Patent No. 2975018 was used.
The water content of the freeze-dried preparation varies depending on conditions such as the degree of vacuum during freeze-drying, temperature, and drying time, but the water content can be controlled by adjusting these as shown in the experimental examples and examples.

  Add 20 mg L-cysteine hydrochloride monohydrate and 50 mg lactose as an excipient to 20 mg titer of amrubicin hydrochloride and dissolve in distilled water for injection so that the concentration of amrubicin hydrochloride is 5 mg / ml The solution was finely adjusted to a pH of about 3 with a small amount of sodium hydroxide and hydrochloric acid, subjected to aseptic filtration, and 10 ml was filled into an 18 ml capacity vial. Put this in a freeze-dryer, and after freezing sufficiently, sublimate and dry the moisture at 20 ° C for 49 hours so that the freeze-dried cake does not melt while controlling the temperature and degree of vacuum, and then seal the rubber stopper and cap. Gave a more stable lyophilized formulation (moisture; 0.9%).

  Add 20 mg L-cysteine hydrochloride monohydrate and 50 mg lactose as an excipient to 20 mg titer of amrubicin hydrochloride and dissolve in distilled water for injection so that the concentration of amrubicin hydrochloride is 5 mg / ml Then, the solution was finely adjusted to a pH of about 3 with a small amount of sodium hydroxide and hydrochloric acid, subjected to sterile filtration, and 4 ml was filled into an 18 ml capacity vial. This is put into a freeze dryer, and after fully frozen, moisture is sublimated and dried at 20 ° C for 24 hours so that the freeze-dried cake does not melt while controlling the temperature and vacuum, and further dried at 40 ° C for 8 hours. Then, a stable freeze-dried preparation was obtained by sealing with a rubber stopper and a cap. (Moisture; 0.7%)

Add 20 mg L-cysteine hydrochloride monohydrate and 50 mg lactose as an excipient to 20 mg titer of amrubicin hydrochloride and dissolve in distilled water for injection so that the concentration of amrubicin hydrochloride is 5 mg / ml The solution was finely adjusted to a pH of about 3 with a small amount of sodium hydroxide and hydrochloric acid, subjected to aseptic filtration, and 10 ml was filled into an 18 ml capacity vial. This was put in a freeze dryer, and after fully frozen, moisture was sublimated and dried at 20 ° C for 37 hours so that the freeze-dried cake would not melt while controlling the temperature and vacuum, and further dried at 40 ° C for 12 hours. Then, a stable freeze-dried preparation was obtained by sealing with a rubber stopper and a cap. (Moisture; 0.6%)
Experimental example 1
L-cysteine hydrochloride monohydrate 3.2 mg and lactose (lactose) 50 mg as an excipient are added to 20 mg titer of amrubicin hydrochloride and dissolved in distilled water for injection. The pH is adjusted with a small amount of sodium hydroxide and hydrochloric acid. Fine tuned to about 3 and sterile filtered and filled into 18 ml vials. Put this in a freeze-dryer, and after freezing sufficiently, sublimate and dry the water over 7 hours so that the freeze-dried cake does not melt while controlling the temperature and vacuum, and then seal the cap with a rubber stopper. Lyophilized formulation A was obtained. Also, after filling the vial and freezing in the same way as described above, after controlling the temperature and degree of vacuum and sublimating and drying the water for 34 hours so that the freeze-dried cake does not melt, the rubber stopper, cap A sealed lyophilized formulation B was obtained. Table 1 shows the results of measurement of moisture (measured by the Karl Fischer method) and degradation products (measured by the HPLC method) of both lyophilized preparations.
Table 1
As can be seen from the above data, it was confirmed that the amount of decomposition products such as deglycosides (2) and deaminates (3) did not change with drying time, but the water content varied greatly with drying time.
Experimental example 2
L-cysteine hydrochloride monohydrate 3.2 mg and lactose (lactose) 50 mg as an excipient are added to 20 mg titer of amrubicin hydrochloride and dissolved in distilled water for injection. The pH is adjusted with a small amount of sodium hydroxide and hydrochloric acid. Fine tuned to about 3 and sterile filtered and filled into 18 ml vials. Place this in a freeze dryer, freeze it sufficiently, sublimate the moisture so that the freeze-dried cake does not melt while controlling the temperature and vacuum, and then dry it thoroughly and freeze-dry by cap sealing the rubber stopper A formulation was obtained (water; 1.3%, deglycosylated (2); 0.63%, deaminated (3); 0.12%). The obtained freeze-dried preparations were conditioned (added with water) to about 3.5% (hydrated preparation A) and about 5% (hydrated preparation B), respectively, and then kept at 40 ° C. for 3 months. Table 2 shows the results of a 6-month storage stability test, and measuring moisture (measured by the Karl Fischer method) and degradation products (measured by the HPLC method).
Table 2
Experimental example 3
The freeze-dried preparations obtained in Example 2 and Example 3 were subjected to a storage stability test at 40 ° C. for 3 months and 6 months to determine moisture (measured by the Karl Fischer method) and degradation products (measured by the HPLC method). Table 3 shows the measurement results.
Table 3
The results of Experimental Example 2 and Experimental Example 3 are shown together in FIG. 1 and FIG.
As can be seen from the above stability data, the amount of deglycosylated (2) produced during long-term storage depends on the water content at the start of the stability test, and the water content in the preparation is in the range of 0 to about 4% by weight. Controlled freeze-dried preparations showed significant improvement in stability compared to preparations with high water content, especially suppression of deglycosides (2), and confirmed that they were sufficiently stable even during long-term storage It was done. Moreover, although there was no big difference in the production amount of a deamination body (3), the tendency which increases a little when water | moisture content decreased was seen.
Experimental Example 4
In a glass beaker, 3.2 mg of L-cysteine hydrochloride monohydrate and 50 mg of lactose (lactose) as an excipient are added to 20 mg titer of amrubicin hydrochloride and dissolved in distilled water for injection. The pH was finely adjusted to about 3 with hydrochloric acid. This solution was placed in a constant temperature bath at 5 ° C., 10 ° C., 15 ° C., and 25 ° C., respectively. The solution was sampled at the start, after 6 hours, and after 24 hours, and the degradation products were quantified by HPLC. Table 4 shows the amount of deglycosylated (2) and deaminated (3) increased from the start.
Table 4
If the deaminated compound (3) is present in an amount of about 1% or more, it will cause turbidity when preparing an injectable solution from an amrubicin lyophilized preparation, and its production must be suppressed to a very small amount. On the other hand, as can be seen from Experimental Example 2 and Experimental Example 3, the amount of deaminated compound (3) increases little by little even during long-term storage of the lyophilized preparation. It is very important to suppress the production amount in the preparation process in a solution state.
As shown in Table 4, when amrubicin hydrochloride is left in a solution state, the amount of deaminated compound (3) produced depends on the temperature of the solution. Therefore, in order to suppress the production amount in the formulation process in the solution state and finally suppress the “content of deaminated compound (3) after long-term storage”, in the formulation production process, in the solution state It is desirable to carry out the formulation step (for example, steps (1) to (3) in the above item [13]) preferably at about 15 ° C. or less, more preferably at about 10 ° C. or less.
Other anthracycline anticancer agents, unlike amrubicin, do not have an amino group at the 9-position of anthracycline, so there is no need to consider the generation of the above deaminated product, and only the deglycosylated product is considered in the formulation process do it.
The production conditions described above enabled mass production of amrubicin lyophilized preparations.

    According to the present invention, a lyophilized preparation of amrubicin useful as a cancer chemotherapeutic agent, which is sufficiently stable even during long-term storage, can be obtained.

Claims (20)

A lyophilized formulation containing amrubicin or a salt thereof, which has the following characteristics:
(1) contains L-cysteine or a salt thereof; and (2) the water content in the preparation is 0 to 3.5 % by weight based on the weight of the lyophilized powder. A stabilizing formulation 請 Motomeko 1, further
(3) The following formula (3) in the preparation:
The stabilized preparation in which the deaminated product represented by the formula is less than 1% by weight based on the weight of the lyophilized powder . The stabilized preparation according to claim 1 or 2, wherein the water content in the preparation is 0.5 to 3.5% by weight based on the weight of the lyophilized powder. The content of L- cysteine or a salt thereof, and against the amrubicin or a salt thereof 100 mg (potency) 0. It is 5-250 mg, The stabilized formulation in any one of Claims 1-3. L- cysteine or its content of salt, amrubicin or stabilizing formulation according to any one of claims 1 to 3 is a pair to 3 to 4 5 mg salt thereof 100 mg (potency). The stabilized preparation according to any one of claims 1 to 5, wherein the salt of amrubicin is hydrochloride. The stabilized preparation according to any one of claims 1 to 6, wherein the salt of L-cysteine is hydrochloride. L-cysteine or a salt thereof is (1 ) 5 to 20 mg of L-cysteine or (2) an L-cysteine salt in an amount corresponding to 100 mg titer of amrubicin hydrochloride. 8. The stabilized preparation according to any one of 7 above. The stabilized preparation according to any one of claims 1 to 8, further comprising an excipient. The stabilized preparation according to claim 9, wherein the excipient is lactose. The aqueous solution containing (a) amrubicin or a salt thereof, and (b) L-cysteine or a salt thereof is prepared, the aqueous solution is subjected to aseptic filtration, and further freeze-dried, so as to be described in any one of claims 1 to 10. A method for producing a stabilized formulation. The manufacturing method of the stabilized formulation in any one of Claims 1-10 including following process (1)-(4):
(1) (a) amrubicin or a salt thereof, and (b) L-cysteine or a salt thereof is dissolved in water to prepare an aqueous solution,
(2) Adjust the pH of the aqueous solution of (1) to 2-5 ,
(3) Aseptically filter the aqueous solution of (2),
(4) The aqueous solution obtained in (3) is freeze-dried. The method according to claim 12 , wherein the salt of amrubicin is hydrochloride. The method according to claim 12 or 13 , wherein the salt of L-cysteine is hydrochloride. In step (2), the pH is adjusted to 2 . 0-3. The manufacturing method according to any one of claims 12 to 14 , which is adjusted to 5. The method according to any one of claims 12 to 15 , wherein the steps (1) to (3) are carried out at 15 ° C or lower. The process according to any one of claims 12 to 15 , wherein the steps (1) to (3) are carried out at 10 ° C or lower. A method for producing a stable lyophilized formulation of amrubicin comprising the following steps (1) to (4):
(1) amrubicin hydrochloride, (the amount of L- cysteine salt equivalent or its) L- cysteine range of 5 to 2 0 mg to respect amrubicin hydrochloride 100mg potency, and the aqueous solution containing the excipients were prepared,
(2) The pH of the aqueous solution of (1) is set to 2 . 0-3. Adjust to 5,
(3) Aseptically filter the aqueous solution of (2),
(4) The aqueous solution obtained in (3) is freeze-dried to obtain a freeze-dried preparation whose water content in the preparation is 0 to 3.5 % by weight with respect to the weight of the freeze-dried powder. Amrubicin hydrochloride, L-cysteine in the range of 5 to 20 mg (or an equivalent amount of L-cysteine salt) with respect to 100 mg titer of amrubicin hydrochloride, and water in the lyophilized preparation containing excipients are lyophilized powder The following formula (2) is adjusted to 0 to 3.5% by weight based on the weight:
The production | generation method of the deglycoside represented by this. 20. The method according to claim 19, wherein the freeze-dried preparation is a freeze-dried preparation in which the deaminated form represented by the formula (3) according to claim 2 in the preparation is less than 1% by weight based on the weight of the freeze-dried powder.